Bicyclo-pyrazoles and pharmaceutical compositions comprising them

Abstract

Bicyclo-pyrazole compounds of formula (I), as herein defined, are useful for treating diseases linked to disregulated protein kinases.

1. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and/or diluent, 
       
         
           
           
               
               
           
         
         wherein
 R is an optionally substituted group selected from the group consisting of —COR′, —COOR′, —CONHR′, —CONR′R″, —NH—C(═NH)NHR′, —SO 2 NHR′ and —SO 2 NR′R″; 
 R 1  is a hydrogen atom or an optionally substituted group selected from the group consisting of R′, —COR′, —COOR′, —CONHR′, —CONR′R″, —NH—C(═NH)NHR′, —SO 2 NHR′ and —SO 2 NR′R″; 
 wherein R′ and R″ are the same or different and are, independently, hydrogen or optionally substituted straight or branched C 1 -C 6  alkyl, aryl, or aryl C 1 -C 6  alkyl, wherein when R′ is hydrogen R″ is not hydrogen, wherein when R″ is hydrogen R′ is not hydrogen and wherein when R 1  is hydrogen, R′ is not hydrogen; 
 Ra, Rb, Rc and Rd are the same or different and are independently selected among hydrogen, or optionally further substituted straight or branched C 1 -C 6  alkyl, aryl, aryl C 1 -C 6  alkyl or —CH 2 OR′ groups, wherein R′ is as above defined, or Ra and Rb and/or Rc and Rd, taken together with the carbon atom to which they are bonded, form an optionally substituted C 3 -C 6  cycloalkyl group; 
 m and n, each independently, represents 0 or an integer from 1 to 2, provided that m+n is lower than, or equal to, 2 (m+n≦2). 
 
       
     
     
       2. A method for treating a mammal, including humans, suffering from a disease caused by and/or associated with an altered protein kinase activity, by administering to said mammal in need thereof a therapeutically effective amount of a bicyclo-pyrazole compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein
 R and R 1 , being the same or different, are independently a hydrogen atom or an optionally substituted group selected from R′, —COR′, —COOR′, —CONHR′, —CONR′R″, —NH—C(═NH)NHR′, —C(═NH)NHR′, —SO 2 NHR′ or —SO 2 NR′R″; wherein R′ and R″, the same or different, are independently selected from hydrogen or optionally further substituted straight or branched C 1 -C 6  alkyl, aryl, C 3 -C 6  cycloalkyl or aryl C 1 -C 6  alkyl or R′ and R″ taken together form a C 4 -C 6  alkylene chain; 
 Ra, Rb, Rc and Rd, being the same or different, are independently selected among hydrogen, optionally further substituted straight or branched C 1 -C 6  alkyl, aryl, aryl C 1 -C 6  alkyl or —CH 2 OR′ groups, wherein R′ is as above defined, or Ra and Rb and/or Rc and Rd, taken together with the carbon atom to which they are bonded, form an optionally substituted C 3 -C 6  cycloalkyl group; 
 m and n, each independently, represents 0 or an integer from 1 to 2, provided that m+n is lower than, or equal to, 2 (m+n≦2); 
 
       
       or a pharmaceutically acceptable salt thereof;
 wherein said disease caused by and/or associated with an altered protein kinase activity is selected from the group consisting of Alzheimer's disease, benign prostate hyperplasia, familial adenomatosis polyposis, neuro-fibromatosis, psoriasis, pulmonary fibrosis, arthritis glomerulonephritis, post-surgical stenosis, restenosis, and cancer, wherein the cancer is selected from the group consisting of leukemia, ovary, colon, breast, lung, and pancreas. 
 
     
     
       3. The method of  claim 2  which provides tumor angiogenesis and metastasis inhibition.